Membrane microdomain switching: a regulatory mechanism of amyloid precursor protein processing.
Neuronal activity has an impact on beta cleavage of amyloid precursor protein (APP) by BACE1 to generate amyloid-beta peptide (Abeta). However, the molecular mechanisms underlying this effect remain to be elucidated. Cholesterol dependency of beta cleavage prompted us to analyze immunoisolated APP-containing detergent-resistant membranes from rodent brains. We found syntaxin 1 as a key molecule for activity-dependent regulation of APP processing in cholesterol-dependent microdomains. In living cells, APP associates with syntaxin 1-containing microdomains through X11-Munc18, which inhibits the APP-BACE1 interaction and beta cleavage via microdomain segregation. Phosphorylation of Munc18 by cdk5 causes a shift of APP to BACE1-containing microdomains. Neuronal hyperactivity, implicated in Abeta overproduction, promotes the switching of APP microdomain association as well as beta cleavage in a partially cdk5-dependent manner. We propose that microdomain switching is a mechanism of cholesterol- and activity-dependent regulation of APP processing in neurons.
Sakurai
Takashi
T
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
Kaneko
Kumi
K
Okuno
Misako
M
Wada
Koji
K
Kashiyama
Taku
T
Shimizu
Hideaki
H
Akagi
Takumi
T
Hashikawa
Tsutomu
T
Nukina
Nobuyuki
N
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002784:Cholesterol / Q000172:deficiency; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D006801:Humans; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D051938:Munc18 Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011328:Prions / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D050827:Syntaxin 1 / Q000378:metabolism; D018800:Thy-1 Antigens / Q000378:metabolism
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D003902:Detergents; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D011328:Prions; D050827:Syntaxin 1; D018800:Thy-1 Antigens; C017474:Lubrol WX; D011092:Polyethylene Glycols; D002784:Cholesterol; D051360:Cyclin-Dependent Kinase 5; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human